Rheumatoid arthritis (RA) is the most common chronic inflammatory disease, affecting up to 1% of the population. Beyond joint pain and stiffness, muscle weakness is among the most prevalent symptoms of RA patients. Weakness affects most major muscle groups and limits basic activities such as walking, sitting and rising from chairs, opening containers, dressing oneself, and personal hygiene. Weakness also contributes to postural instability in RA, predisposing individuals to fall-related injuries, and dramatically lessens the overall quality of life. There is no drug therapy for RA-related weakness, no clinical standard of care to address this debilitating problem. The goal of this project is to define processes that cause weakness in RA and identify biological targets for future drug development. Weakness far exceeds muscle atrophy in RA patients. Therefore, the focus of our project is loss of contractile function as reflected by specific force, i.e, force per cross-sectional area. Our experimental model proposes that RA increases muscle exposure to proinflammatory cytokines that stimulate production of nitric oxide (NO) derivatives and reactive oxygen species (ROS) by muscle fibers. The resulting oxidative stress depresses specific force and causes weakness. Interventions that disrupt this chain of events are expected to preserve specific force, opposing RA-related weakness. We will test this model by using muscles from RA patients and a well-established mouse model of RA (collagen-induced arthritis, CIA) to address four specific aims: Specific Aim 1. To identify cytokines essential for RA-induced weakness. Specific Aim 2. To define changes in skeletal muscle oxidant production caused by RA. Specific Aim 3. To define cellular mechanisms of contractile dysfunction in RA. Specific Aim 4.To test therapeutic approaches for preserving muscle function in RA.